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非酒精性脂肪性肝病在研新药的进展

徐昆 张旭 李瑛 胡振斌

徐昆, 张旭, 李瑛, 等. 非酒精性脂肪性肝病在研新药的进展[J]. 临床肝胆病杂志, 2021, 37(7): 1699-1703. DOI: 10.3969/j.issn.1001-5256.2021.07.047
引用本文: 徐昆, 张旭, 李瑛, 等. 非酒精性脂肪性肝病在研新药的进展[J]. 临床肝胆病杂志, 2021, 37(7): 1699-1703. DOI: 10.3969/j.issn.1001-5256.2021.07.047
XU K, ZHANG X, LI Y, et al. Advances in investigational new drugs for nonalcoholic fatty liver disease[J]. J Clin Hepatol, 2021, 37(7): 1699-1703. DOI: 10.3969/j.issn.1001-5256.2021.07.047
Citation: XU K, ZHANG X, LI Y, et al. Advances in investigational new drugs for nonalcoholic fatty liver disease[J]. J Clin Hepatol, 2021, 37(7): 1699-1703. DOI: 10.3969/j.issn.1001-5256.2021.07.047

非酒精性脂肪性肝病在研新药的进展

DOI: 10.3969/j.issn.1001-5256.2021.07.047
基金项目: 

国家十三五“艾滋病和病毒性肝炎等重大传染病防治”科技重大专项基金 2018ZX10725505-002

详细信息
    通讯作者:

    胡振斌,huzhenbin123@163.com

  • 中图分类号: R575.5

Advances in investigational new drugs for nonalcoholic fatty liver disease

Funds: 

The National Thirteenth Five-Year Plan"Prevention and Treatment of Major Infectious Diseases such as AIDS and Viral Hepatitis" Science and Technology Major Special Fund Project 2018ZX10725505-002

  • 摘要: 非酒精性脂肪性肝病(NAFLD)是全世界最常见的肝脏疾病,与肥胖、胰岛素抵抗和其他代谢性疾病密切相关。目前尚无批准用于治疗的药物,常规的生活方式管理也难以对疾病产生积极的影响。对目前在研的代谢调节剂、抗炎抗氧化剂及抗纤维化剂等NAFLD治疗药物进行了综述,归纳总结了其临床研究结果,为NAFLD的临床治疗及药物研发提供新思路。

     

  • [1] SVEN MF, PIERRE B, MANAL FA, et al. A randomised, double-blind, placebo-controlled, multi-centre, dose-range, proof-of-concept, 24-week treatment study of lanifibranor in adult subjects with non-alcoholic steatohepatitis: Design of the NATIVE study[J]. Contemp Clin Trials, 2020, 98: 106170. DOI: 10.1016/j.cct.2020.106170.
    [2] KABBANY MN, CONJEEVARAM SELVAKUMAR PK, WATT K, et al. Prevalence of nonalcoholic steatohepatitis-associated cirrhosis in the United States: An analysis of national health and nutrition examination survey data[J]. Am J Gastroenterol, 2017, 112(4): 581-587. DOI: 10.1038/ajg.2017.5.
    [3] POLYZOS SA, KOUNTOURAS J, MANTZOROS CS. Obesity and nonalcoholic fatty liver disease: From pathophysiology to therapeutics[J]. Metabolism, 2019, 92: 82-97. DOI: 10.1016/j.metabol.2018.11.014.
    [4] FRANCQUE S, SZABO G, ABDELMALEK MF, et al. Nonalcoholic steatohepatitis: The role of peroxisome proliferator-activated receptors[J]. Nat Rev Gastroenterol Hepatol, 2021, 18(1): 24-39. DOI: 10.1038/s41575-020-00366-5.
    [5] BOUGARNE N, WEYERS B, DESMET SJ, et al. Molecular actions of PPARα in lipid metabolism and inflammation[J]. Endocr Rev, 2018, 39(5): 760-802. DOI: 10.1210/er.2018-00064.
    [6] STAELS B, RUBENSTRUNK A, NOEL B, et al. Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis[J]. Hepatology, 2013, 58(6): 1941-1952. DOI: 10.1002/hep.26461.
    [7] RATZIU V, HARRISON SA, FRANCQUE S, et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening[J]. Gastroenterology, 2016, 150(5): 1147-1159.e5. DOI: 10.1053/j.gastro.2016.01.038.
    [8] WESTEROUEN VAN MEETEREN MJ, DRENTH J, TJWA E. Elafibranor: A potential drug for the treatment of nonalcoholic steatohepatitis (NASH)[J]. Expert Opin Investig Drugs, 2020, 29(2): 117-123. DOI: 10.1080/13543784.2020.1668375.
    [9] TANG JT, MAO YM. Development of new drugs for the treatment of nonalcoholic steatohepatitis[J]. J Dig Dis, 2020, 21(1): 3-11. DOI: 10.1111/1751-2980.12830.
    [10] COLCA JR, McDONALD WG, ADAMS WJ. MSDC-0602K, a metabolic modulator directed at the core pathology of non-alcoholic steatohepatitis[J]. Expert Opin Investig Drugs, 2018, 27(7): 631-636. DOI: 10.1080/13543784.2018.1494153.
    [11] HARRISON SA, ALKHOURI N, DAVISON BA, et al. Insulin sensitizer MSDC-0602K in non-alcoholic steatohepatitis: A randomized, double-blind, placebo-controlled phase Ⅱb study[J]. J Hepatol, 2020, 72(4): 613-626. DOI: 10.1016/j.jhep.2019.10.023.
    [12] JONES D, BOUDES PF, SWAIN MG, et al. Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: A double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study[J]. Lancet Gastroenterol Hepatol, 2017, 2(10): 716-726. DOI: 10.1016/S2468-1253(17)30246-7.
    [13] GOTTLIEB A, CANBAY A. Why bile acids are so important in non-alcoholic fatty liver disease (NAFLD) progression[J]. Cells, 2019, 8(11). DOI: 10.3390/cells8111358.
    [14] PELLICCIARI R, COSTANTINO G, CAMAIONI E, et al. Bile acid derivatives as ligands of the farnesoid X receptor. Synthesis, evaluation, and structure-activity relationship of a series of body and side chain modified analogues of chenodeoxycholic acid[J]. J Med Chem, 2004, 47(18): 4559-4569. DOI: 10.1021/jm049904b.
    [15] NEUSCHWANDER-TETRI BA, LOOMBA R, SANYAL AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): A multicentre, randomised, placebo-controlled trial[J]. Lancet, 2015, 385(9972): 956-965. DOI: 10.1016/S0140-6736(14)61933-4.
    [16] ZOBAIR Y, VLAD R, ROHIT L, et al. GS-06-positive results from REGENERATE: A phase 3 international, randomized, placebo-controlled study evaluating obeticholic acid treatment for NASH[J]. J Hepatol, 2019, 70(1): e5. DOI: 10.1016/SO618-8278(19)30006-4.
    [17] PATEL K, HARRISON SA, ELKHASHAB M, et al. Cilofexor, a nonsteroidal FXR agonist, in patients with noncirrhotic NASH: A phase 2 randomized controlled trial[J]. Hepatology, 2020, 72(1): 58-71. DOI: 10.1002/hep.31205.
    [18] HARRISON SA, BASHIR MR, LEE KJ, et al. A structurally optimized FXR agonist, MET409, reduced liver fat content over 12 weeks in patients with non-alcoholic steatohepatitis[J]. J Hepatol, 2021, 75(1): 25-33. DOI: 10.1016/j.jhep.2021.01.047.
    [19] KEVIN K, WANG YJ, RANDALL H, et al. FRI-313-A novel farnesoid X receptor agonist, TERN-101, reduces liver steatosis, inflammation, ballooning and fibrosis in a murine model of non-alcoholic steatohepatitis[J]. J Hepatol, 2019, 70(1): e534.
    [20] FIORUCCI S, BIAGIOLI M, SEPE V, et al. Bile acid modulators for the treatment of nonalcoholic steatohepatitis (NASH)[J]. Expert Opin Investig Drugs, 2020, 29(6): 623-632. DOI: 10.1080/13543784.2020.1763302.
    [21] BERNSMEIER C, MEYER-GERSPACH AC, BLASER LS, et al. Glucose-induced glucagon-like Peptide 1 secretion is deficient in patients with non-alcoholic fatty liver disease[J]. PLoS One, 2014, 9(1): e87488. DOI: 10.1371/journal.pone.0087488.
    [22] ARMSTRONG MJ, GAUNT P, AITHAL GP, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study[J]. Lancet, 2016, 387(10019): 679-690. DOI: 10.1016/S0140-6736(15)00803-X.
    [23] NAUCK M, FRID A, HERMANSEN K, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: The LEAD (liraglutide effect and action in diabetes)-2 study[J]. Diabetes Care, 2009, 32(1): 84-90. DOI: 10.2337/dc08-1355.
    [24] KATSIKI N, ATHYROS VG, KARAGIANNIS A, et al. Semaglutide, lipid-lowering drugs, and NAFLD[J]. Lancet Diabetes Endocrinol, 2017, 5(5): 329-330. DOI: 10.1016/S2213-8587(17)30109-2.
    [25] AMBERY P, PARKER VE, STUMVOLL M, et al. MEDI0382, a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes: A randomised, controlled, double-blind, ascending dose and phase 2a study[J]. Lancet, 2018, 391(10140): 2607-2618. DOI: 10.1016/S0140-6736(18)30726-8.
    [26] FRIAS JP, NAUCK MA, VAN J, et al. Efficacy and tolerability of tirzepatide, a dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist in patients with type 2 diabetes: A 12-week, randomized, double-blind, placebo-controlled study to evaluate different dose-escalation regimens[J]. Diabetes Obes Metab, 2020, 22(6): 938-946. DOI: 10.1111/dom.13979.
    [27] TONG L. Acetyl-coenzyme A carboxylase: Crucial metabolic enzyme and attractive target for drug discovery[J]. Cell Mol Life Sci, 2005, 62(16): 1784-1803. DOI: 10.1007/s00018-005-5121-4.
    [28] HARRIMAN G, GREENWOOD J, BHAT S, et al. Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats[J]. Proc Natl Acad Sci U S A, 2016, 113(13): e1796-e1805. DOI: 10.1073/pnas.1520686113.
    [29] STIEDE K, MIAO W, BLANCHETTE HS, et al. Acetyl-coenzyme A carboxylase inhibition reduces de novo lipogenesis in overweight male subjects: A randomized, double-blind, crossover study[J]. Hepatology, 2017, 66(2): 324-334. DOI: 10.1002/hep.29246.
    [30] LOOMBA R, KAYALI Z, NOUREDDIN M, et al. GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease[J]. Gastroenterology, 2018, 155(5): 1463-1473.e6. DOI: 10.1053/j.gastro.2018.07.027.
    [31] DEGIROLAMO C, SABBÀ C, MOSCHETTA A. Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23[J]. Nat Rev Drug Discov, 2016, 15(1): 51-69. DOI: 10.1038/nrd.2015.9.
    [32] HARRISON SA, RINELLA ME, ABDELMALEK MF, et al. NGM282 for treatment of non-alcoholic steatohepatitis: A multicentre, randomised, double-blind, placebo-controlled, phase 2 trial[J]. Lancet, 2018, 391(10126): 1174-1185. DOI: 10.1016/S0140-6736(18)30474-4.
    [33] ZHANG F, YU L, LIN X, et al. Minireview: Roles of fibroblast growth factors 19 and 21 in metabolic regulation and chronic diseases[J]. Mol Endocrinol, 2015, 29(10): 1400-1413. DOI: 10.1210/me.2015-1155.
    [34] NOUREDDIN M, VIPANI A, BRESEE C, et al. NASH leading cause of liver transplant in women: Updated analysis of indications for liver transplant and ethnic and gender variances[J]. Am J Gastroenterol, 2018, 113(11): 1649-1659. DOI: 10.1038/s41395-018-0088-6.
    [35] KRAUSE C, GROHS M, EL GAMMAL AT, et al. Reduced expression of thyroid hormone receptor β in human nonalcoholic steatohepatitis[J]. Endocr Connect, 2018, 7(12): 1448-1456. DOI: 10.1530/EC-18-0499.
    [36] HARRISON SA, BASHIR MR, GUY CD, et al. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: A multicentre, randomised, double-blind, placebo-controlled, phase 2 trial[J]. Lancet, 2019, 394(10213): 2012-2024. DOI: 10.1016/S0140-6736(19)32517-6.
    [37] FERNÁNDEZ-RAMOS D, LOPITZ-OTSOA F, DELACRUZ-VILLAR L, et al. Arachidyl amido cholanoic acid improves liver glucose and lipid homeostasis in nonalcoholic steatohepatitis via AMPK and mTOR regulation[J]. World J Gastroenterol, 2020, 26(34): 5101-5117. DOI: 10.3748/wjg.v26.i34.5101.
    [38] SUMIDA Y, YONEDA M, OGAWA Y, et al. Current and new pharmacotherapy options for non-alcoholic steatohepatitis[J]. Expert Opin Pharmacother, 2020, 21(8): 953-967. DOI: 10.1080/14656566.2020.1744564.
    [39] LEE YA, WALLACE MC, FRIEDMAN SL. Pathobiology of liver fibrosis: A translational success story[J]. Gut, 2015, 64(5): 830-841. DOI: 10.1136/gutjnl-2014-306842.
    [40] LEFERE S, DEVISSCHER L, TACKE F. Targeting CCR2/5 in the treatment of nonalcoholic steatohepatitis (NASH) and fibrosis: Opportunities and challenges[J]. Expert Opin Investig Drugs, 2020, 29(2): 89-92. DOI: 10.1080/13543784.2020.1718106.
    [41] FRIEDMAN SL, RATZIU V, HARRISON SA, et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis[J]. Hepatology, 2018, 67(5): 1754-1767. DOI: 10.1002/hep.29477.
    [42] YOON YC, FANG Z, LEE JE, et al. Selonsertib inhibits liver fibrosis via downregulation of ASK1/MAPK pathway of hepatic stellate cells[J]. Biomol Ther (Seoul), 2020, 28(6): 527-536. DOI: 10.4062/biomolther.2020.016.
    [43] CHALASANI N, ABDELMALEK MF, GARCIA-TSAO G, et al. Effects of belapectin, an inhibitor of galectin-3, in patients with nonalcoholic steatohepatitis with cirrhosis and portal hypertension[J]. Gastroenterology, 2020, 158(5): 1334-1345.e5. DOI: 10.1053/j.gastro.2019.11.296.
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  • 收稿日期:  2020-11-23
  • 修回日期:  2021-01-11
  • 刊出日期:  2021-07-20
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